Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation

Mitochondrial function affects many aspects of cellular physiology, and, most recently, its role in epigenetics has been reported. Mechanistically, how mitochondrial function alters DNA methylation patterns in the nucleus remains ill defined. Using a cell culture model of induced mitochondrial DNA (mtDNA) depletion, in this study we show that progressive mitochondrial dysfunction leads to an early transcriptional and metabolic program centered on the metabolism of various amino acids, including those involved in the methionine cycle. We find that this program also increases DNA methylation, which occurs primarily in the genes that are differentially expressed. Maintenance of mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation in the context of mtDNA loss rescues methionine salvage and polyamine synthesis and prevents changes in DNA methylation and gene expression but does not affect serine/folate metabolism or transsulfuration. This work provides a novel mechanistic link between mitochondrial function and epigenetic regulation of gene expression that involves polyamine and methionine metabolism responding to changes in the tricarboxylic acid (TCA) cycle. Given the implications of these findings, future studies across different physiological contexts and in vivo are warranted.

线粒体功能影响细胞生理学的诸多方面，近期更有研究揭示其在表观遗传学（epigenetics）中的作用。从机制层面而言，线粒体功能如何改变细胞核内的DNA甲基化模式仍未明确。本研究采用诱导型线粒体DNA（mtDNA）耗竭的细胞培养模型，证实进行性线粒体功能障碍会触发以多种氨基酸代谢为核心的早期转录与代谢程序，其中涵盖参与甲硫氨酸循环的氨基酸。研究发现，该程序同时会升高DNA甲基化水平，且甲基化主要发生在差异表达的基因中。在mtDNA耗竭的情况下维持还原型烟酰胺腺嘌呤二核苷酸（NADH）的氧化状态，可挽救甲硫氨酸补救途径与多胺合成，并阻止DNA甲基化与基因表达的改变，但不会影响丝氨酸/叶酸代谢及转硫途径。本研究揭示了线粒体功能与基因表达表观遗传调控之间的新型机制关联，该关联涉及响应三羧酸（TCA）循环变化的多胺与甲硫氨酸代谢。鉴于本研究结果的潜在意义，未来需在不同生理环境及体内模型中开展相关研究。